Self-organization of polymers has been utilized in obtaining well-defined supramolecular assemblies such as micelles, vesicles, fibers, helical superstructures, nanoparticles and macroscopic tubes. (Zhang, et al. 1995 Science 268, 1728; Zhang, et al. 1996 Science 272, 1777; Hest, et al. 1995 Science 268, 1592; Discher, et al. 2002 Science 297, 967; Hartegrink, et al. 2001 Science 294, 1684; Claussen, et al. 2003 J. Am. Chem. Soc. 125, 12680; Conrnelissen, et al. 1998 Science, 280, 1427; McCarthy, et al. 2005 Nano Lett. 12, 2552; Yan, et al. 2004 Science, 303, 65.) These self-assembled superstructures are of interest in a variety of areas ranging from material science to biology. (Stupp, et al. 1997 Science 277, 1242: Savic, et al. 2003 Science 300, 615.)
A daunting challenge remains in developing nanoscale polymeric assemblies that combine two or more of nanoassemblies to achieve a hybrid or a composite nanostructure. The difficulties are primarily due to the structural requirements associated with the formation of assemblies. Most supramolecular assemblies are achieved by balancing the presence of two incompatible functional groups within the same molecule. (Israelachvili, et al. 1976 J. Chem. Soc., Faraday Trans. 2, 72, 1525; Discher, et al. 1999 Science 284, 1143; Tang, et al. 2008 Science 322, 429.) When this balance is disturbed, the fidelity of assembly is affected. Classical example includes the need for hydrophilic-lipophilic balance in amphiphilic molecules to maintain well-defined nanoscale assemblies. (Azagarsamy, et al. 2010 J. Am. Chem. Soc. 132, 4550; Azagarsamy, et al. 2009 J. Am. Chem. Soc. 131, 14184; Amir, et al. 2009 J. Am. Chem. Soc. 131, 13949; Guo, et al. 2012 J. Am. Chem. Soc. 134, 10244.) A major difficulty arises from the fact that composite nanostructures, made from two different nanoassemblies, would likely disturb that critical balance needed for the fidelity of the individual nanostructures.
Delivering guest molecules accurately to target sites with controlled release is of particular importance in medical therapeutics and biomedical diagnostics. (Allen, et al. 2004 Science 303, 1818-1822; Farokhzad, et al. 2009 ACS Nano 3, 16-20; Rozhkova 2011 Adv. Mater. 23, H136-H150.) A variety of nanocontainers have been studied for controllable delivery since nanocontainers have the potential to administer guest molecules, as well as enhance the therapeutic effect while possessing low inherent toxicity. (Pan, et al. 2012 J. Am. Chem. Soc. 134, 5722-5725; Shiah, et al. 1999 J. Control Release 61, 145-157; Bae, et al. 2005 Bioconjug. Chem. 16, 122-130; Duncan 2003 Nature Rev. Drug. Discov. 2, 347-360; Rothenfluh, et al. 2008 Nature Mater. 7, 248-254.)
Water-soluble polymer nanoparticles, such as micelles, nanogels and polymersomes, are promising candidates for nanocontainers due to their stability profile, high biocompatibility and facile functionalization. (Christian, et al. 2009 Nature Mater. 8, 243-249; Kataoka, et al. 2001 Adv. Drug Deliv. Rev. 47, 113-131; Cabral, et al. 2007 J. Control. Release 121, 146-155; Matsumura, et al. 2009 Cancer Sci. 100, 572-579; Plummer, et al. 2011 Br. J. Cancer 104, 593-598; Aliabadi, et al. 2006 Expert Opin. Drug Deliv. 3, 139-162; Nishiyama, et al. 2006 Pharmacol. Therapeut. 112, 630-648; Cabral, et al. 2001 Nature Nanotech. 6, 815-823; Nochi, et al. 2010 Nature Mater. 9, 572-578; Ryu, et al. 2010 J. Am. Chem. Soc. 132, 17227-17235; Oh, et al. 2008 Prog. Polym. Sci. 33, 448-477; Akiyoshi, et al. 1997 Macromolecules 30, 857-861; Kageyama, et al. 2008 Cancer Sci. 99, 601-607; Ryu, et al. 2010 J. Am, Chem. Soc. 132, 8246-8247; Discher, et al. 2002 Science 297, 967-973; Meng, et al. 2009 Biomacromolecules 10, 197-209; Iatrou, et al. 2007 Biomacromolecules 8, 2173-2181; Zhou, et al. 2005 J. Am. Chem. Soc. 127, 10468-10469.)
Nanocontainers are typically constructed by both hydrophobic and hydrophilic components, which endow them with high hydrophobic guest encapsulation capability and excellent solubility in water. Encapsulation and release of the guest are two faces of one contradiction. Stable encapsulation easily results in an extremely low release rate, while desirable release rate is always a consequence of unstable encapsulation. To resolve this conflict, nanocarriers with stimulus-response properties have been designed to achieve triggered and targeted release.
Several strategies have been investigated for the triggered release, such as pH, temperature, light and redox sensitivities. (Du, et al. 2005 J. Am. Chem. Soc. 127, 17982-17983; Kakizawa, et al. 2002 Adv. Drug Deliver. Rev. 54, 203-222; Lee. et al. 2007 J. Am. Chem. Soc. 129, 15096-15097; Martien, et al. 2010 Nature Mater. 9, 101-113; Li, et al. 2006 Angew. Chem. Int. Ed. 45, 5792-5795; Qin, et al. 2006 Adv. Mater. 18, 2905-2909; Goodwin, et al. 20051 Am. Chem. Soc. 127, 9952-9953; Kostiainen, et al. 2010 Nature Chem. 2, 394-399; Power-Billard, et al. 2004 Angew. Chem., Int. Ed. 43, 1260-1264; Lin, et al. 2007 Bioconjugate Chem. 18, 138-145; Thorpe, et al. 1987 Cancer Res. 15, 5924-5931; Klaikherd, et al. 2009 J. Am. Chem. Soc. 131, 4830-4838.) Unfortunately, many of these systems just respond automatically to the environmental signals and make some corresponding changes in chemical or physical properties, which can easily cause inaccurate and uncontrollable delivery.
To overcome these drawbacks, researchers have tried to install guiding devices on nanocontainers. It has been reported that decorating the surface of nanocontainers with ligands, such as peptide, protein and antibody, can assist selective targeted delivery. This strategy, however, demands a high degree of control over ligand density to achieve high selectivity. (Rothenfluh, et al. 2008 Nature Mater. 7, 248-254; Ashley, et al. 2011 Nature Mater. 10, 389-397; Strauch, et al. 2011 J. Am. Chem. Soc. 133, 16346-16349; Farokhzad, et al. 2006 Proc. Natl Acad. Sci. USA 103, 6315-6320; Pastan, et al. 2006 Nat. Rev. Cancer 6, 559-565.) For example, in the tumor cell targeted delivery system, a high density of targeted ligand is required to improve affinity and delivery efficiency. On the other hand, a high ligand density can enhance nonspecific interations with endothelial and other non-cancer cells and increase immunogenicity, leading to opsonization-mediated clearance of nanocontainers. (Peer, et al. 2007 Nature Nanotech. 2, 751-760; Ferrari 2008 Nature Nanotech. 3, 131-132.)
Thus, a major unmet need remains for an intelligent nano-vehicle with accurate and controlled delivery of multiple guests. In particular, it is highly desirable to have composite supramolecular nanostructures that are hybrids of and independently retain key features in two or more distinct nanoassembly components.